2. Academic Validation
  3. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

  • Sci Transl Med. 2018 Nov 14;10(467):eaar7047. doi: 10.1126/scitranslmed.aar7047.
Stephen T Buckley 1,  Tine A Bækdal 2,  Andreas Vegge 3,  Stine J Maarbjerg 2,  Charles Pyke 3,  Jonas Ahnfelt-Rønne 3,  Kim G Madsen 3,  Susanne G Schéele 3,  Tomas Alanentalo 3,  Rikke K Kirk 3,  Betty L Pedersen 3,  Rikke B Skyggebjerg 3,  Andrew J Benie 3,  Holger M Strauss 3,  Per-Olof Wahlund 3,  Simon Bjerregaard 3,  Erzsébet Farkas 4,  Csaba Fekete 4 5,  Flemming L Søndergaard 2,  Jeanett Borregaard 2,  Marie-Louise Hartoft-Nielsen 2,  Lotte Bjerre Knudsen 3
Affiliations

Affiliations

  • 1 Novo Nordisk A/S, 2760 Måløv, Denmark. spby@novonordisk.com.
  • 2 Novo Nordisk A/S, 2860 Søborg, Denmark.
  • 3 Novo Nordisk A/S, 2760 Måløv, Denmark.
  • 4 Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary.
  • 5 Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
PMID: 30429357 DOI: 10.1126/scitranslmed.aar7047
Abstract

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic Enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

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